CN107441095A - ACV mitigates the new medical use of toxicity of irinotecan - Google Patents
ACV mitigates the new medical use of toxicity of irinotecan Download PDFInfo
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- CN107441095A CN107441095A CN201710718193.8A CN201710718193A CN107441095A CN 107441095 A CN107441095 A CN 107441095A CN 201710718193 A CN201710718193 A CN 201710718193A CN 107441095 A CN107441095 A CN 107441095A
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- Prior art keywords
- irinotecan
- acv
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- diarrhoea
- tumor patient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides anti-herpes simplex virus medicament ACV to prevent or/and treat the retardance diarrhoea caused by a kind of antineoplastic, purposes in the medicine of intestinal dysfunction caused by diarrhoea, wherein, described antineoplastic refers to Irinotecan or its HCPT (SN 38) of 7 ethyl of active metabolite 10.In the present invention, ACV drug action is clear and definite, can effectively alleviate late-onset diarrhea, protects gut function.
Description
Technical field
The invention belongs to chemical medicine, and in particular to anti-herpes simplex virus medicament ACV and antineoplastic
Irinotecan is used in combination, and reduces the toxic reaction of Irinotecan, increases the constitution of tumor patient, that is, improves tumor patient tolerance
The dosage of Irinotecan, extend the time that tumor patient uses Irinotecan.
Background technology
Irinotecan is clinically used for treating advanced colorectal cancer, with 5 FU 5 fluorouracil and folinic acid (LV) therapeutic alliance the past
The late stage colorectal cancer patients of chemotherapy are not received；As single drug, treat through the Endodontic failure of chemotherapy regimen containing 5 FU 5 fluorouracil
Patient.Irinotecan hydrochloride 180mg/m2Drip-feed 30-90 minutes, the 1st day；LV 400mg/m2Should be in irinotecan hydrochloride
Given immediately after infusion, the time of instiling is identical, the 1st day；5-FU 400mg/m2Intravenous injection, the 1st day, then 1200 mg/m2/d
× 2 days Intravenous Infusion (total amount 2400mg/m2, it is transfused 46-48 hours).Repeat within every 2 weeks.Irinotecan it is dose-limiting
Toxicity is that retardance suffers from diarrhoea (medication occurs after 24 hours).The medicine being used in combination with antineoplastic Irinotecan is found, is subtracted
Suffered from diarrhoea caused by few Irinotecan, it is necessary to reduce the gut function barrier caused by diarrhoea.
ACV is a kind of purine nucleoside analogs of synthesis.The various senses being mainly used in caused by herpes simplex virus
Dye, available for initial or recurring skin, mucous membrane, the herpes simplex virus of external genital organs infection and immune deficiency person's generation
(herpes simplex virus, HSV) infects, but anti-HSV drug acyclovirs and antineoplastic Irinotecan or its work
Property metabolin SN38 (SN-38) be used in combination, prevent or treat the poison for reducing Irinotecan or SN-38
Property reaction, reduce and suffer from diarrhoea caused by Irinotecan or SN-38, reduce under the dietary amount that the intestinal dysfunction caused by the diarrhoea occurs
Drop, increase the constitution of tumor patient, improve tumor patient tolerance Irinotecan or SN-38 dosage, extend tumor patient
Report is had no using the effect of Irinotecan or SN-38 times.The present inventor has found ACV with resisting by largely studying
Tumour medicine Irinotecan or SN-38 are used in combination, and can significantly reduce Irinotecan or SN-38 toxic reaction, suppress anti-
Suffered from diarrhoea caused by tumour medicine Irinotecan or SN-38, reduce the gut function caused by diarrhoea and hinder, increase dietary amount, increase is swollen
The constitution of knurl patient, tumor patient tolerance Irinotecan or SN-38 dosage are improved, extends tumor patient and is replaced using Yi Li
The time of health or SN-38.Based on this, the present inventor invented ACV combine with Irinotecan or SN-38 use, reduce
The toxic reaction of Irinotecan or SN-38, diarrhoea caused by reducing Irinotecan or SN-38, reduces the intestines work(caused by diarrhoea
Can the dietary amount that occurs of obstacle decline, increase the constitution of tumor patient, improve making for tumor patient tolerance Irinotecan or SN-38
With dosage, extend time of the tumor patient using Irinotecan or SN-38.
The content of the invention
The invention provides ACV and antineoplastic Irinotecan or SN-38 to be used in combination, and reduces Irinotecan
Or SN-38 toxic reaction, that is, diarrhoea caused by reducing Irinotecan or SN-38, reduce the gut function caused by diarrhoea and hinder
Hinder, tolerance of the increase tumor patient to Irinotecan or SN-38, extend time of the tumor patient using Irinotecan or SN-38,
Increase Irinotecan or SN-38 dosage.
The dosage scope of ACV provided by the invention is 200mg~5000mg, preferably 200mg~2500mg.
Specific embodiment
Influence of the ACV of experimental example 1 to toxicity caused by Irinotecan medication
1.1 medicines and reagent
ACV (purity 99.3%, is bought in Shanghai Han Xiang bio tech ltd)
Irinotecan hydrochloride (purity 99.5%, is bought in Shanghai Han Xiang bio tech ltd)
Experimental animal：SPF level C57 mouse, male, body weight 20g-22g, Beijing dimension limited public affairs of tonneau China's experimental animal technology
Take charge of Experimental Animal Center to provide, animal quality certification number is：SCXK (capital) 2012-0001.
1.2 experimental methods and result
1.2.1 toxic model mouse caused by Irinotecan continuous use prepares, is grouped and is administered
Male mice 70, body weight 20-22g, takes 60, is divided into 6 groups, i.e. normal group, Irinotecan group, and Irinotecan+
ACV 40mg/kg groups, Irinotecan+ACV 100mg/kg groups, Irinotecan+ACV 500mg/kg groups, she
Vertical to replace health+ACV 1000mg/kg groups, every mouse peritoneal injection Irinotecan 50mg/kg, each ACV group is being given
Irinotecan 50mg/kg gives the ACV of corresponding dosage simultaneously.Irinotecan is continuously injected intraperitoneally 4 days, each ACV
Group successive administration 5 days, calculates body weight and food ration between administration phase, and statistics Irinotecan causes the scoring of mouse late-onset diarrhea, commented
Valency scale is as follows:Stool is normal:0 point；Defecate dilute soft：1 point；Wet and unfashioned stool, there is moderateperianal's
Coating coloring：2 points；Water sample, water sample is with the serious coloring of crissum：3 points, calculate the average mark of modeling 5 days.Compare Irinotecan
Group and the difference of Irinotecan+ACV each group, progress T inspections between group.
1.2.2 experimental result
Tables 1 and 2 result shows Irinotecan intraperitoneal injection 50mg/kg, continuous injection 4 days, it is small can substantially to mitigate model
Body weight, the food ration of mouse, increase by 5 days average diarrheal scores (compared with normal group, p<0.01)；Irinotecan+ACV 40
Mg/kg groups, Irinotecan+ACV 100mg/kg groups, Irinotecan+ACV 500mg/kg groups, Irinotecan+Ah
VCV 1000mg/kg gastric infusions group substantially increases the body weight of model mice, food ration, reduces by 5 days average diarrheal scores
(compared with Irinotecan group, p<0.5 or p<0.01).Irinotecan+ACV 500mg/kg gastric infusions group is replaced with Yi Li
Health+ACV 1000mg/kg gastric infusion groups compare, and body weight, food ration without obvious increase model mice, reduce by 5 balances
Equal diarrheal scores (p>0.05).
Influence of the ACV of table 1 to toxic model mouse weight and food ration caused by Irinotecan continuous use
| Group | Body weight (g) | 5 days total food rations (g) |
| Normal group | 34.1±1.3 | 4.6±0.4 |
| Irinotecan group | 22.3±1.8# | 1.4±0.4# |
| Irinotecan+ACV 40mg/kg | 24.4±1.7* | 1.8±0.4* |
| Irinotecan+ACV 100mg/kg | 26.5±2.2** | 2.4±0.6** |
| Irinotecan+ACV 500mg/kg | 28.3±1.9** | 3.3±0.8** |
| Irinotecan+ACV 1000mg/kg | 28.4±2.1** | 3.3±0.7** |
#, p<0.01, compared with normal group；*, p<0.05,**, p<0.01, compared with Irinotecan group
The influence that the ACV of table 2 scores toxic model diarrhea of mouse caused by Irinotecan continuous use
| Group | 5 days average diarrheal scores |
| Normal group | 0.1±0.1 |
| Irinotecan group | 2.6±0.3# |
| Irinotecan+ACV 40mg/kg | 2.2±0.4* |
| Irinotecan+ACV 100mg/kg | 1.4±0.4** |
| Irinotecan+ACV 500mg/kg | 0.9±0.5** |
| Irinotecan+ACV 1000mg/kg | 0.9±0.4** |
#, p<0.01, compared with normal group；*, p<0.05,**, p<0.01, compared with Irinotecan group
The ACV of experimental example 2 influences on the tumor bearing nude mice life cycle of Irinotecan medication
2.1 medicines and reagent
ACV (purity 99.3%, is bought in Shanghai Han Xiang bio tech ltd)
Irinotecan hydrochloride (purity 99.5%, is bought in Shanghai Han Xiang bio tech ltd)
Experimental animal：BALB/c nude mice SPF levels, male, body weight 20g-22g, Beijing dimension tonneau China experimental animal technology have
Limit company Experimental Animal Center provides, and animal quality certification number is：SCXK (capital) 2012-0001.
2.2 experimental methods and result
2.2.1 the tumor bearing nude mice packet and administration of Irinotecan continuous use
Tumor bearing nude mice 70, body weight 20-22g, takes 60, is divided into 6 groups, i.e. normal group, Irinotecan group, and Irinotecan+
ACV 40mg/kg groups, Irinotecan+ACV 100mg/kg groups, Irinotecan+ACV 500mg/kg groups, she
Vertical to replace health+ACV 1000mg/kg groups, in addition to normal group animal, the mg/kg of Irinotecan 60 is injected intraperitoneally in each group mouse,
Each ACV group is giving Irinotecan 60mg/kg while is giving the ACV of corresponding dosage.The continuous abdominal cavity of Irinotecan
Injection 4 days, each ACV group successive administration 7 days, animal survival time is calculated, at the end of 7 days, animal is not dead, is designated as 144
Hour.Compare the animal survival time difference of Irinotecan group and Irinotecan+ACV each group.T inspections are carried out between group.
2.2.2 experimental result
The result of table 3 shows Irinotecan intraperitoneal injection 60mg/kg, continuous injection 4 days, can substantially increase animal dead, subtract
Few time-to-live (compared with normal group, p<0.01)；Irinotecan+ACV 40mg/kg groups, Irinotecan+ACV
100mg/kg groups, Irinotecan+ACV 500mg/kg groups, Irinotecan+ACV 1000mg/kg gastric infusion groups are bright
Aobvious reduction animal dead, and the increase time-to-live (compared with Irinotecan group, p<0.5 or p<0.01), Irinotecan+ACV
500mg/kg gastric infusions group, Irinotecan+ACV 1000mg/kg gastric infusion groups are without animal dead.
The ACV of table 3 influences on the tumor bearing nude mice time-to-live of Irinotecan continuous use
| Group | Mean survival time (h) |
| Normal group | 144 |
| Irinotecan group | 90±39# |
| Irinotecan+ACV 40mg/kg | 129±20* |
| Irinotecan+ACV 100mg/kg | 135±16** |
| Irinotecan+ACV 500mg/kg | 144** |
| Irinotecan+ACV 1000mg/kg | 144** |
#, p<0.01, compared with normal group；*, p<0.05,**, p<0.01, compared with Irinotecan group.
Claims (5)
1. a kind of ACV or its pharmaceutically acceptable salt are used to prepare prevention or/and treatment and drug combination, medicine is reduced
The purposes of toxic action, the medicine are Irinotecan or its active metabolite SN38.
2. purposes according to claim 1, it is characterised in that the toxicity of the medicine is diarrhoea, gut function caused by diarrhoea
Obstacle.
3. according to the purposes described in claim 1-2, it is characterised in that treatment late period is used in combination with Irinotecan in ACV
Colorectal cancer, the dosage of tumor patient tolerance Irinotecan is improved, extend the time that tumor patient uses Irinotecan.
4. according to the purposes described in claim 1-2, it is characterised in that ACV is combined with SN38 and made
With treatment advanced CRC, the dosage of tumor patient tolerance SN38 is improved, extending tumor patient makes
With the time of SN38.
5. according to any described applications of claim 1-4, it is characterised in that the dosage scope of ACV be 200mg~
5000mg。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710718193.8A CN107441095A (en) | 2017-08-21 | 2017-08-21 | ACV mitigates the new medical use of toxicity of irinotecan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710718193.8A CN107441095A (en) | 2017-08-21 | 2017-08-21 | ACV mitigates the new medical use of toxicity of irinotecan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107441095A true CN107441095A (en) | 2017-12-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710718193.8A Withdrawn CN107441095A (en) | 2017-08-21 | 2017-08-21 | ACV mitigates the new medical use of toxicity of irinotecan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107441095A (en) |
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2017
- 2017-08-21 CN CN201710718193.8A patent/CN107441095A/en not_active Withdrawn
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| WW01 | Invention patent application withdrawn after publication | ||
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Application publication date: 20171208 |